Beta-carotene is a micronutrient found in a variety of fruits and vegetables. Epidemiological studies have suggested that beta-carotene may prevent the development of human tumors, including breast cancer. The mechanisms responsible for mediating the anti-cancer properties of beta- carotene are unknown. Our laboratory has a long standing interest in the nuclear receptors for retinoic acid, specifically the RARs and the RXRs. Recently, we have demonstrated that one receptor, RARbeta2 is induced by retinoic acid in human mammary epithelial cells. We have also shown that RARbeta2 can function as a tumor suppressor gene. It is known that beta- carotene can be metabolized to both all-trans- and 9-cis-retinoic acid, ligands known to transcriptionally activate retinoid receptors. In two highly interactive RO-1's (Peacocke - Project I and Krinsky - Project II) we hope to test the hypothesis that beta-carotene and its metabolites serves as a dietary source of ligands that induce a specific signal transduction pathway, regulated by RARbeta2, that inhibits the proliferation of breast epithelial cells in humans: This pathway, therefore, may be one mechanism by which beta-carotene mediates its anti- carcinogenic effect. Furthermore, we hope to identity changes that occur in this pathway during the transformation of a normal breast epithelial cell to a cancerous one. These studies should provide a molecular framework for the design of nutritional interventions using beta-carotene that will prevent the development of breast cancer in humans.